Much of our past research on growth has been concerned with the ras oncogene and its positive regulators, the Ras-specific guanine nucleotide exchange factors (Ras-GNEFs), which play a key role in signal transduction. We have recently turned our attention to E-cadherin and its role in the regulation of growth and signaling. E-cadherin is an essential adhesion protein that is also a tumor suppressor frequently silenced in tumors. Originally described as a structural protein, E-cadherin has more recently been recognized to regulate signaling. The principal biologically relevant signaling molecule thus far implicated as being regulated by E-cadherin is Beta-catenin, which binds non-covalently to E-cadherin and is a key component of the Wnt signaling pathway. However, although adhesion is the hallmark function of E-cadherin, its regulation of Beta-catenin does not depend on the adhesive function of E-cadherin. We have now found that E-cadherin can negatively regulate, in an adhesion-dependent manner, the ligand-dependent activation of divergent classes of receptor tyrosine kinases, including EGFR/Neu, IGF1R, and c-Met. By contrast, E-cadherin did not regulate a constitutively active mutant receptor tyrosine kinase (Neu*) or the ligand-dependent activation of LPA receptors or muscarinic receptors, which are two G protein coupled receptors. E-cadherin dependent adhesion restricted the mobility of EGFR-CFP in the plasma membrane and eliminated high affinity EGF and IGF-1 binding sites, thus impairing the ability of the ligands to activate their cognate receptors. The results indicated that negative regulation of receptor tyrosine kinases by their soluble ligands is physiologic, specific, and adhesion-dependent. Since receptor tyrosine kinases have been implicated in multiple cellular processes, including nutrition, growth, and differentiation, the data imply that E-cadherin can regulate these processes. Abrogation of receptor tyrosine kinase regulation may also contribute to the frequent silencing of E-cadherin in tumors.